Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine

Abstract

The alkaloid drug berberine (BBR) was recently described to decrease plasma cholesterol and triglycerides (TGs) in hypercholesterolemic patients by increasing expression of the hepatic low density lipoprotein receptor (LDLR). Using HepG2 human hepatoma cells, we found that BBR inhibits cholesterol and TG synthesis in a similar manner to the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide 1-b-ribofuranoside (AICAR). Significant increases in AMPK phosphorylation and AMPK activity were observed when the cells were incubated with BBR. Activation of AMPK was also demonstrated by measuring the phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK, correlated with a subsequent increase in fatty acid oxidation. All of these effects were abolished by the mitogen-activated protein kinase kinase inhibitor PD98059. Treatment of hyperlipidemic hamsters with BBR decreased plasma LDL cholesterol and strongly reduced fat storage in the liver. These findings indicate that BBR, in addition to upregulating the LDLR, inhibits lipid synthesis in human hepatocytes through the activation of AMPK. These effects could account for the strong reduction of plasma TGs observed with this drug in clinical trials.-Brusq, J-M., N. Ancellin, P. Grondin, R. Guillard, S. Martin, Y. Saintillan, and M. Issandou. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine.

Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity

“…Intraperitoneal administration of BBR into obese db/db mice reduced body weight without a significant effect on food intake ( Fig. 1, A and B), which is consistent with previous reports (5,9,16,19,38). In addition, we observed that BBR lowered the RQ ratio and increased energy expenditure (Fig.…”

“…We and others (9,19,38) have reported that BBR reduces body weight, causes a significant improvement in glucose tolerance, and improves insulin action in obese and/or diabetic subjects by activating AMPK. A large body of evidence indicates that BBR enhances insulin sensitivity and reduces hyperlipidemia (5,9,16,38). Thus it is plausible to speculate that this mechanism might be applied therapeutically to treat fatty liver and hyperlipidemia.…”

Co-administration of berberine and plant stanols synergistically reduces plasma cholesterol in rats

“…Reductions of plasma TAG by BBR were also observed in other studies in rats with diabetes and nephritis [42,43,47]. Results from several in vitro studies have demonstrated that BBR decreases TAG levels through regulating fatty acid metabolism toward the downregulation of adipogenesis [51][52][53]. BBR upregulates the phosphorylation of the AMPactivated protein kinase (AMPK), which phosphorylates and inactivates acetyl-CoA carboxylase (ACC) [51,52].…”

“…Results from several in vitro studies have demonstrated that BBR decreases TAG levels through regulating fatty acid metabolism toward the downregulation of adipogenesis [51][52][53]. BBR upregulates the phosphorylation of the AMPactivated protein kinase (AMPK), which phosphorylates and inactivates acetyl-CoA carboxylase (ACC) [51,52]. The inactivation of ACC results in the inhibition of fatty acid synthesis but the enhancement of fatty acid oxidation.…”

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

“…Acute activation of AMPK has been shown to result in the phosphorylation and inactivation of acetyl-CoA carboxylase, a key enzyme regulating the balance between fatty acid biosynthesis and oxidation [13,48]. Inactivation of acetyl-CoA carboxylase leads to a decrease in fatty acid synthesis and a concomitant increase in fatty acid oxidation, resulting in depletion of IMTG stores [49,50].…”